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Metabolic Syndrome

Because of its complexity, this set of disorders teems with opportunities for drug development, but regulatory criteria for therapeutic outcomes are still lacking

November 22, 2004 | A version of this story appeared in Volume 82, Issue 47


Nowadays, with heightened concern about obesity, people who are lean might feel complacent: If excess weight means disease, then normal weight must mean health. Not always, because a silent killer called the metabolic syndrome can strike anyone, overweight or not.

The metabolic syndrome is a set of disorders that significantly increases the risk of heart disease. Its biochemical underpinnings are tremendously complicated and are still being worked out. What's certain now is that among its major components are excess weight, high blood pressure, dyslipidemia (high levels of triglycerides and low levels of high-density lipoproteins in the blood, leading to buildup of plaque in blood vessel walls), and insulin resistance (the inability of muscle, fat, and liver cells to absorb glucose in response to insulin, leading to excess glucose in the blood). Each is a risk factor for heart disease, but a person with several of these disorders--that is, a person with the metabolic syndrome--is vastly more at risk.

Increasingly, the medical community is identifying and treating people with the metabolic syndrome. In the clinic, diagnosis is based on easily measurable parameters: fat accumulation around the waist, blood pressure, levels of key lipids, and levels of glucose. Lifestyle contributes enormously to abnormalities in these parameters, and doctors admonish patients to eat right and exercise as the first line of defense. But even for people who dutifully eat right and exercise, those measures may not be enough to halt the metabolic syndrome. Doctors and patients hope that pharmaceuticals might help.

A daily pill to treat the metabolic syndrome would likely be far less expensive than saving a patient who's having a heart attack. According to the Centers for Disease Control & Prevention, almost 6 million hospitalizations and 950,000 deaths in the U.S. each year are due to cardiovascular disease. For 2003, the economic effects are projected at $351 billion.

In the U.S., it is estimated that 47 million adults are likely to have the metabolic syndrome; the number of people actually diagnosed and receiving treatment would be far smaller. With the rapidly rising incidence of obesity among children and youth, the number of adults with the metabolic syndrome is likely to swell. According to CDC, about 16% of six- to 19-year-olds in 1999–2002 (more than 9 million youngsters, total) were overweight. In this group, the metabolic syndrome is highly prevalent, studies show.

The causes of the syndrome are not yet fully understood. Genetics is a factor. A recent study has shown that a cluster of abnormalities similar to those in the metabolic syndrome can be caused by a single mutation in a mitochondrial gene. Lifestyle is a factor. Physical inactivity and diets that generate high levels of fat in the blood correlate strongly to the metabolic syndrome. Age is a factor. If you are at least 35 years old, there is a 25% probability that you have the syndrome; by age 60, the probability increases to 40%.

Several mechanisms may operate concurrently to give rise to the metabolic syndrome. Obesity is high on the list of some researchers, including Samuel Klein, a professor of medicine at Washington University, St. Louis. "Although, right now, obesity is not one of the criteria for the metabolic syndrome, anyone who has a large waist circumference that meets the criteria is almost always obese," he says.

It is now clear that obesity is not just a matter of excess weight, because fat cells do not merely store fat: They send out bioactive molecules with powerful effects throughout the body. Some of these are low-molecular-weight proteins that induce inflammation, now considered a major cause of cardiovascular disease.

For example, tumor necrosis factor- (TNF-) activates inflammatory changes in vascular tissue that promote the adhesion of monocytes, which are a type of white blood cell, to the thin lining of the blood vessels. When a monocyte stuck to the blood vessel penetrates the lining, it becomes a macrophage that feeds on low-density lipoproteins in the plasma. The accumulation of macrophages begins an atherosclerotic plaque. TNF- also interferes with insulin signaling and causes insulin resistance.

Angiotensinogen is the precursor to angiotensin II, which constricts blood vessel walls and raises blood pressure. In addition, it enhances macrophage accumulation as well as the metabolism of nitric oxide into free radicals. NO counters the effects of angiotensin II: It dilates blood vessel walls and protects them from macrophage adhesion.

Plasminogen activator inhibitor-1 slows the dissolution of blood clots. High levels of PAI-1 make it more difficult to remove blood clots, increasing the risk of a heart attack or stroke.

Other chemical messengers from fat cells help regulate energy balance. For example, leptin signals the brain that the body has enough fat stores and encourages the body to burn calories faster.

SO FAR, only one bioactive molecule from fat cells is known to be exclusively beneficial: Adiponectin inhibits insulin resistance as well as inflammation. According to Osama Hamdy, director of the obesity clinical program at Harvard University's Joslin Diabetes Center, adiponectin and TNF- have opposing effects on insulin sensitivity and cardiovascular risk. High TNF- and low adiponectin are associated with obesity, insulin resistance, and coronary artery disease. Weight loss raises adiponectin, making adiponectin "a very valid future drug candidate" for obesity, insulin resistance, and coronary artery disease, he says.

"The metabolic syndrome occurs in people who are lean and people who are obese," Hamdy explains. "You will be surprised, but 18% of men and 22% of women who are of normal weight or slightly overweight have the metabolic syndrome. You can be of normal weight but have a high percentage of body fat. And then it matters how much of that fat is visceral and how much is subcutaneous. Fat in the deep visceral area is the most dangerous." Unlike the fat under the skin, visceral fat is more easily mobilized and is a richer source of proinflammatory proteins such as TNF-. When hydrolyzed, visceral fat releases free fatty acids. When these reach the liver, they are converted to triglycerides and stored.

An even more important cause of the metabolic syndrome may be insulin resistance, according to others, including Gerald M. Reaven, emeritus professor of medicine at Stanford University. According to Reaven, insulin resistance varies considerably from person to person. About half of the variability is due to genetics and half to lifestyle.

In 1988, Reaven proposed that individuals with a cluster of abnormalities related to insulin resistance are at significantly higher risk for cardiovascular disease. He named the cluster of risk factors Syndrome X. As the list of abnormalities associated with insulin resistance expanded and the cardiovascular community acknowledged the importance of insulin resistance as a risk factor for heart disease, the cluster became known as the metabolic syndrome.

Researchers agree that insulin resistance is central to the metabolic syndrome. When target cells are unresponsive to insulin, the pancreas responds by pouring even more insulin into the bloodstream, leading to high levels of the hormone in the blood, a condition called compensatory hyperinsulinemia. The high level of insulin in the blood forces glucose into cells but also starts the events leading to arterial damage and eventually a heart attack. Under these conditions, a person may not manifest either diabetes or heart disease but could well be on the way to either or both.

In general, excess insulin causes problems because insulin affects many other processes. For example, it stimulates the uptake of amino acids and increases the permeability of cells to key ions, such as potassium. In muscle cells, it promotes storage of glucose as glycogen. It also induces the secretion of angiotensin II, a peptide hormone that constricts arteries and raises blood pressure, according to H. James Harwood Jr., a principal research investigator for cardiovascular and metabolic diseases at Pfizer. So when insulin levels go up, hypertension follows, he explains.

In the liver, insulin promotes the synthesis of free fatty acids. However, excess fat makes liver cells insulin resistant. Metformin, a popular drug to treat diabetes, works by improving the liver's sensitivity to insulin, Hamdy says. When free fatty acids are exported from the liver, they are taken up by other tissues, including fat (adipose) tissue, which stores free fatty acids as triglycerides.

On the other hand, insulin also inhibits the breakdown of fat in adipose tissues. Thus, insulin spares fat, and excess insulin will spare more fat. Tissues with too much fat produce fewer insulin receptors and are more resistant to insulin. In a vicious cycle, the pancreas responds by pumping more insulin until the insulin-producing cells die from exhaustion. Type 2 diabetes ensues.

Under conditions of insulin resistance and compensatory hyperinsulinemia, the liver makes more very low density lipoprotein (VLDL). Among the lipoproteins that the body uses to transport fat, VLDL contains the greatest amount of triglycerides. Release of VLDL from the liver raises the levels of trigylcerides in the blood. And when VLDL is converted to low-density lipoprotein, levels of LDL rise. VLDL also tends to exchange some of its triglycerides with the cholesterol contained in high-density lipoprotein (HDL)--so-called good cholesterol. This reduces the levels of HDL cholesterol. High triglycerides, high LDL, and low HDL all increase the risk of a heart attack.

The impact of fat on insulin resistance is even more pronounced during periods of stress, which releases the stress hormones adrenaline and cortisol. Adrenaline in turn stimulates the hydrolysis of fat in fat tissue, raising the amount of free fatty acids in circulation, which eventually end up in the liver. On the other hand, cortisol builds back the fat in fat tissue.

UNCHECKED, insulin resistance will progress to diabetes, and glucose will flood the bloodstream. People with diabetes are likely to suffer damage to the eyes, nerves, and kidney; be more susceptible to infection, ulceration, and gangrene; and eventually develop heart disease. These complications are probably due to the reactivity of the excess glucose in the bloodstream. In the reaction called glycation, glucose attaches to various proteins and causes them to cross-link and form so-called advanced glycation end products. These are known to trap LDL particles in artery walls and have been linked to cataract formation and reduced kidney function.

This oversimplified picture of the metabolic syndrome belies the complexity of the interconnections among insulin action, fat storage, energy metabolism, and cardiovascular disease. As research advances, many more links will surface.

The clinical situation also is not straightforward. Most doctors accept that the metabolic syndrome must be diagnosed and treated, but patients who feel fine may resist treatment, adopting a wait-and-see attitude instead. Furthermore, according to a 2004 survey of cardiologists, endocrinologists, and primary-care physicians by Decision Resources, Waltham, Mass., many health plans will not reimburse expenses for treatment of the metabolic syndrome. One reason that is cited is the perception that the syndrome is a lifestyle issue.

The survey, titled "Metabolic Syndrome in the United States: Current Medical Practice and Market Opportunities," also finds that what's keeping a small minority of physicians from acknowledging the syndrome as a medical condition requiring treatment is the lack of consensus on its definition.

Diagnosis of the metabolic syndrome is based on comparing a patient's values for risk factors against levels defined by several bodies. The most widely cited set of criteria is that of the U.S. National Cholesterol Education Program Adult Treatment Panel III (ATP III). According to ATP III, a patient has the metabolic syndrome if he or she meets the criteria for at least three of five parameters:

◾ Waist circumference 40 inches (men) or 35 inches (women)
◾ Triglycerides 150 mg/dL
◾ HDL cholesterol 40 mg/dL (men) or 50 mg/dL (women)
◾ Blood pressure 130/85 mm Hg
◾ Fasting glucose 110 mg/dL

That definition is straightforward, but not everyone is happy with it. For example, at the 2nd International Conference on Targeting Metabolic Syndrome, organized by IBC USA Conferences and held last May in Boston, David C. Robbins, director for endocrine research at Eli Lilly, pointed out three problems: The definition does not work well with certain ethnic groups, it gives equal weight to each parameter, and it does not factor in the effect of age on risk.

The definition also does not address the core issue of insulin resistance. According to Reaven, some people may not meet the criteria for the metabolic syndrome but still be insulin resistant. If insulin resistance is the root of metabolic syndrome and if the ATP III criteria cannot reliably identify insulin-resistant individuals, then reliance on the criteria could be disastrous, as the insulin resistance of those who are missed would likely progress to diabetes and heart disease.

In defense of the ATP III criteria, they were defined so that doctors can diagnose the risk for cardiovascular disease through simple tests. Insulin resistance and the abnormalities it fosters clearly are important risk factors for cardiovascular disease, but at present no simple test for insulin resistance exists. The American Diabetes Association has initiated an effort to standardize the insulin assay and hopes to have recommendations by next summer.

If the purpose of diagnosis is to enable treatment, Reaven questions the soundness of treating a patient who is diagnosed with the metabolic syndrome and not a patient who satisfies only two criteria. In his view, any patient with an abnormal value for any of the five ATP III parameters should be treated to correct that abnormal value.

As for treatment, doctors overwhelmingly recommend losing weight through proper nutrition and regular exercise. Eating right means eating modest amounts--not supersize servings--and avoiding foods that contain or generate high levels of fat. Physical activity ensures that calories consumed are expended. According to Hamdy, reducing weight by as little as 7% significantly improves insulin sensitivity because when the body sheds fat, the first to go is the bad visceral fat.


BECAUSE LOSING weight is hard for many people, what's often done is to treat the individual diseases, Klein says. "Treating the individual components is a sign that we have failed to change lifestyle adequately to reduce the harmful indications of the metabolic syndrome," he says. For their part, pharmaceutical companies are filling their pipelines with candidates targeting the individual diseases associated with the metabolic syndrome: obesity, dyslipidemia, hypertension, and diabetes. At the same time, they are repositioning drugs already in their portfolio as potential therapy for the syndrome.

The metabolic syndrome is attractive to drug companies because opportunities for intervention are numerous, says Sreten Bogdanovic, a managing partner at Biophoenix, a biomedical market and technology consultancy based in Coventry, England. Bogdanovic and his colleague Beata Langlands are coauthors of the report "Metabolic Syndrome: New Opportunities in Diagnostics and Therapeutics," published early this year by D&MD Publications, Westborough, Mass. "Also, the kind of drugs that are needed must be taken for a long time to maintain their effects, not like antibiotics that are taken only for a fixed period," Bogdanovic says.

He explains that drug companies currently seem to compartmentalize drug development for the metabolic syndrome into the three areas that offer the most commercial opportunities: obesity, diabetes, and dyslipidemia. Drugs to treat obesity typically aim to restrict food intake or increase energy expenditure. Some limit the absorption of nutrients. Two drugs are already in the U.S. market: Abbott's sibutramine suppresses the appetite, whereas Roche's orlistat reduces the absorption of dietary fat. Widespread use of both is limited by side effects. The D&MD report lists more than 200 development programs for obesity treatments. Some of those, including rimonabant, were discussed at the metabolic syndrome conference this past May in Boston.

Rimonabant, an advanced candidate of the French pharmaceutical company Sanofi-Synthélabo, is a selective antagonist of the CB1 receptor of the endocannabinoid system, which is a key player in the regulation of energy homeostasis. The drug was developed on the basis that marijuana smokers often experience hunger pangs. The thinking was that if cannabinoids trigger hunger, blocking their receptors would suppress the appetite. The drug is in Phase III clinical trials for obesity and also is a candidate for smoking cessation and alcohol addiction.

Rimonabant created a buzz last summer as a key driver in Sanofi-Synthélabo's acquisition of its French-German rival Aventis. According to news accounts, Sanofi-Synthélabo "needed more muscle to sell" the potential blockbuster, and Aventis, with its "powerful sales force" especially in the U.S. market, could fill that need. The new company, Sanofi-Aventis, is projected to launch the drug in 2006 under the brand name Acomplia.

Also being investigated for obesity are the antiepileptic drugs zonisamide and topiramate. Their therapeutic effect is based on interfering with seizure-inducing out-of-control electrical impulses in the nerve cells of the brain. Patients taking these agents report being full sooner when eating and being disinterested in sweets. The idea is that overeating might be triggered by out-of-control electrical impulses to the brain's pleasure centers, and interfering with those signals might reduce the craving for food.

The attention being paid to obesity is not detracting from the search for better drugs to treat diabetes and other abnormalities leading to cardiovascular disease. For the latter, drug development is focused on lipid-modifying and antihypertensive agents. For diabetes, the focus is on insulin sensitizers--agents that overcome insulin resistance--and insulin secretory agents--compounds that help maintain the insulin-secreting capacity of the pancreas (C&EN, Oct. 25, page 59).

Given that the metabolic syndrome may be considered a prediabetic state and that diabetes almost always progresses to cardiovascular disease, drugs to treat dyslipidemia, hypertension, and diabetes have the potential to keep the syndrome in check. The D&MD report provides a comprehensive list of candidates in the pipeline.

Among the notable ones for diabetes are the PPAR (peroxisome proliferator-activated receptor) agonists. PPARs are ligand-activated receptors that regulate the expression of genes involved in the storage and use of dietary fats. Three subtypes have been identified: , , and . The natural ligands of the PPARs are not known, but synthetic ligands for PPAR- and PPAR- have an insulin-sensitizing effect.

Many of those ligands belong to the compound class called thiazolidinediones, also known as glitazones. At present, two glitazones are approved for the treatment of diabetes: GlaxoSmithKline's rosiglitazone and Takeda/Eli Lilly's pioglitazone. Neither is advised for patients with a history of heart, liver, or kidney disease.

The D&MD report lists 25 programs to develop PPAR agonists for diabetes. Two candidates are in Phase III clinical trials: AstraZeneca's tesaglitazar and Bristol-Myers Squibb's muraglitazar. Both are dual-acting--that is, they activate PPAR- and PPAR-. Development of Novo Nordisk's balaglitazone, a PPAR- agonist licensed from Dr. Reddy's Research Foundation, in India, has been terminated.

In Phase II clinical trials is a GlaxoSmithKline PPAR pan-agonist identified only as compound 677954. PPAR pan-agonists activate all the PPAR subtypes. At GSK, a team led by William R. Oliver, a senior investigator in the department of metabolic diseases, was the first to prepare a selective ligand for PPAR-. At the metabolic syndrome meeting in Boston, Oliver suggested that PPAR pan-agonists "may address the cluster of risk factors characteristic of the metabolic syndrome." Indeed, PPAR agonists also are candidates for treatment of dyslipidemia, with almost 30 programs in place, according to the D&MD report.

ONE REASON for the compartmentalized drug development is that many studies are showing that an agent designed to treat one disease also neutralizes risk factors associated with the other two. For example, the cholesterol-lowering drugs called statins have antiinflammatory properties. The antidiabetic agent pioglitazone alleviates dyslipidemia. Thus, companies with drugs for one indication are looking for other applications in the milieu of the metabolic syndrome. Meanwhile, treating several aspects of this syndrome by combining agents targeting different risk factors in one pill is already being practiced. Pfizer's Caduet, launched early this year, is an example. It is a combination of two blockbuster Pfizer drugs: the antihypertensive agent amlodipine (Norvasc) and the cholesterol-lowering atorvastatin (Lipitor). A two-in-one pill makes compliance easier for the patient and reduces production costs for the drug company, Harwood says.

Whether doctors will prescribe two-in-one treatments for the metabolic syndrome remains to be seen. The Decision Resources survey indicates that significant hurdles are in the way.

Most of the physicians surveyed would not prescribe Caduet for metabolic syndrome patients with normal LDL levels "because there is not enough clinical data to support" such use.

Furthermore, the specialists--cardiologists and endocrinologists--"are not too keen because of dosing issues," says Carole D. Gleeson, the survey report's author. They want more control over dosing of the individual drugs because their patients are difficult to treat.

Agonists of peroxisome proliferates activated receptors have been in clinical trials.
Agonists of peroxisome proliferates activated receptors have been in clinical trials.

In addition, among the associated complications of the metabolic syndrome, diabetes is what concerns doctors the most, the survey shows. "A lot of doctors say that having diabetes is equivalent to having a cardiovascular disease; the risk of a heart attack is the same," Gleeson says. For patients with diabetes only, the most prescribed drug is metformin, but for diabetics with a second complication, especially dyslipidemia, doctors may also prescribe an insulin sensitizer, such as rosiglitazone or pioglitazone. Doctors seeking to treat the metabolic syndrome might give a bigger welcome to a drug that combines a glucose-lowering agent and a lipid-lowering agent.

Another reason for compartmentalizing drug development for the metabolic syndrome is that no one yet knows what a drug to treat this syndrome should achieve. Right now, no guidance exists as to what combination of abnormalities a drug ideally should treat and to what degree each abnormality should be treated, Harwood says. Until regulatory agencies, including the Food & Drug Administration, know how incremental changes in multiple risk factors will impact the overall risk for cardiovascular disease among patients with the metabolic syndrome, they cannot rule on what is an approvable drug for the syndrome, he explains.

The studies needed to reach these definitions have not been done, but there is some movement in that direction. "That the medical community and FDA are now willing to look at drugs in combination and that investigators are starting to look at the benefits of simultaneous submaximal treatment of multiple abnormalities" are positive signs, Harwood says.

In the meantime, doctors are hoping to neutralize the metabolic syndrome with drugs to treat obesity, hypertension, dyslipidemia, and diabetes. If and when regulatory guidelines become available, the first likely drug applications would be for combinations of agents, each targeting one of the four diseases.

But is it necessary to target all the risk factors? Could there be a magic bullet, one agent in one tablet targeting only one risk factor? Perhaps, and it may be already at hand.


As Bogdanovic and Langlands write, "To gain the most benefit from modifying multiple metabolic risk factors, the underlying insulin-resistant state must become a target of therapy." Insulin sensitizers are already on the market to treat diabetes. But as the D&MD report states: "Currently, there is insufficient data to support widespread pharmacological therapy of insulin-resistant individuals. Drug companies will need to demonstrate the effectiveness of novel insulin sensitizers in large-scale population trials."

Finally, the metabolic syndrome has important implications for drug development in general. According to Bogdanovic, many drugs are not "metabolism friendly." For example, high blood pressure is often treated with agents that impair glucose utilization. Some agents to treat epilepsy, diabetes, and depression promote weight gain. Such effects have predictable adverse repercussions.

"Ignoring metabolism friendliness can be expensive for a drugmaker," Bogdanovic says. The most recent example is Merck's Vioxx, for treatment of arthritis. Its side effects of elevating blood pressure and impairing glucose utilization have now been shown to have "dire cardiovascular consequences," he points out. "The drug industry and prescribers need to focus on making and using more metabolism-friendly alternatives."

LAYERED Whole-body images such as these allow measurements of total body fat, among other parameters. On the far left, images show all the tissue compartments, each represented by a unique color, for a lean person (top) and an overweight person (bottom). The next images in each series show what's left after removal of subcutaneous adipose tissue (green), muscle tissue (red), and residual tissue (yellow). In the rightmost images, visceral adipose tissue is shown in gray and intramuscular adipose tissue in pink. Images were composed computationally from magnetic resonance imaging scans of cross-sectional slices of a whole body. COURTESY OF THE IMAGE READING CENTER, ST. LUKE'S HOSPITAL OF COLUMBIA UNIVERSITY MEDICAL CENTER


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